Neramexane, also known as 1-amino-1,3,3,5,5-pentamethylcyclohexane, has been found to be useful in the therapy of various diseases including tinnitus disease. Neramexane appears to be therapeutically effective after oral administration. Typically, neramexane is administered at least twice a day during continuous therapy in order to ensure that therapeutically effective plasma concentrations are maintained and fluctuation of the plasma levels is limited.
Modified release solid oral dosage forms permit the modified release of the active ingredient over an extended period of time in an effort to maintain therapeutically effective plasma levels over similarly extended time intervals and/or to modify other pharmacokinetic properties of the active ingredient.
WO 2007/062815 A1 suggests an oral modified release dosage form comprising a therapeutically effective amount of neramexane, and at least one release-controlling excipient.
WO 2007/009691 suggests mixtures of specific pyrazole derivatives in combination with an anti-addictive agent such as neramexane in the form of microtablets.
EP 1 684 729 suggests a multilayer pharmaceutical form for controlled active ingredient release. Neramexane is mentioned as active ingredient among a variety of other compounds.
US 2007/0231397 A1 suggests pharmaceutical forms having a stable active ingredient release profile. Neramexane is mentioned as active ingredient among a variety of other compounds.
US 2008/0312587 A1 suggests a system for orally administering a solid to dementia sufferer. The antidementia agent may be neramexane.
WO 2009/033649 relates to interval and/or maintenance therapy employing neramexane, wherein neramexane may be introduced into microspheres or microcapsules e.g. based on polyglycolic acid.
US 2007/0141148 relates to oral modified release dosage forms of neramexane.
US 2006/002999 relates to immediate release dosage forms of 1-aminocyclohexanes such as neramexane.
WO 2006/058059 relates to methods and compositions for administering an NMDA receptor antagonist such as memantine to a subject.
WO 2006/138227 relates to immediate release dosage forms containing memantine.
Modified release dosage forms are also known from other active agents. Minitablets comprising a release-controlling excipient are e.g. known from Orfiril®, an agent for the treatment of primary (idiopathic) epilepsy.
Release dosage forms are available either as single unit (nondivided formulation) or as multiple unit (divided formulation) dosage forms. The single unit dosage forms usually refer to diffusion-controlled systems where the drug is dissolved or dispersed throughout a solid matrix and the release of the drug is controlled or sustained either by incorporating a suitable filler within the matrix or by coating the matrix with swellable or nonswellable polymer film(s). The former case is known as a monolithic system where the diffusion of a drug through a matrix is the rate-limiting step. In monolithic preparations made of polymers the drug release is commonly governed by the swelling rate of the polymer matrix. In the second case, the diffusion of the drug through the polymer coating or layer of the system is the rate controlling step.
Multiple unit dosage forms are essential where drug-excipient or drug-drug interaction are possible in a single unit formulation. They are also known to have less variance in transit time through the gastrointestinal tract than single unit dosage forms. The multiple unit dosage forms usually are based on subunits such as granules, pellets, or minitablets. They are usually delivered in hard gelatin capsules or transformed into tablets that disintegrate immediately in aqueous media of the GI tract, releasing the modified release units.
Multiple unit dosage forms may offer advantages and disadvantages over the single unit systems. On the one hand, multiple unit forms may offer more predictable gastric emptying, gastric emptying less dependent on the state of nutrition, a high degree of dispersion in the digestive tract, less variability of absorption, and a lower risk of dose dumping. On the other hand, multiple unit preparations may exhibit several disadvantages. Their manufacturing is more complicated and more expensive, the filling of gelatin capsules is difficult to accomplish especially in the case where different subunits are involved, and the preparation process of minitablets necessitates extra care and fine adjustments of tabletting machines.
Although the debate on the particular advantages of the two formulations (single- and multiple unit) has been going on for a long time in the literature, it has not produced any definite conclusion on the performance of those formulations until now, and the differences in behavior are controversial (AAPS PharmSciTech. 2000; 1(4): article 34).